The synthesis of 2,3,5-trisubstituted phenols

Synthetic route to 2,3,5-trisubstituted phenols based on two-step [1+2+3] construction of the phenol backbone from 1-[(trimethylsilyl)methyl]-1 H -1,2,3-benzotriazole, aliphatic or arylacetic acid chlorides and chalcones or α , β -unsaturated- γ -diketones was developed. 2,3,5-Trisubstituted phenols 8 , 9a-e , 10a-d , 12a-e were successfully synthesized.


Results and Discussion
The reactions of the intermediates 3a-g or 4 and α,β-unsaturated ketones are discussed in several separate subsections according to the proposed reaction mechanisms reported earlier. 6i) The reactions of intermediates 3a-c with the symmetrical chalcones 5a,b or c.Treatment of the mixture of each intermediate 3a-c and the appropriate chalcone 5a, b or c in nbutanol with 2 equiv. of potassium tert-butoxide and refluxing for 48 h gave 2,3,5-trisubstituted phenols 9a-e in good yields (Table 1).The structures of 9a-e were assigned by their 1 H NMR and 13 C NMR spectra: only one new set of signals was found.
In the 1 H NMR of 9a, the three singlets at 2.07 ppm, 2.26 ppm and 2.30 ppm were assigned to the three methyl groups of 9a; in the 13 C NMR of 9a, the signals of these groups appear at 12.8 ppm, 21.0 ppm and 21.1 ppm.In the 1 H NMR and 13 C NMR spectra of the phenols 9b-e, we have also found only one set of proton and carbon signals in each case, this confirming that the sequence afforded a single product.There are some differences in the acidity of the active methylenes alpha to the carbonyl in the intermediates 3a-c, depending on whether R is an aliphatic group or an aromatic group, but that had no affect on the reactions of symmetrical chalcones 5a,b,c, which gave only one final product.
(ii) The reactions of intermediates 3a, c, or d with unsymmetrical chalcones 6a,b, or c.When the intermediates 3a,c or d reacted with the chalcones 6a-c under the same conditions as used for the preparation of 9a-e, the results obtained varied as follows.a) The reaction of the intermediate 3c or 3d with chalcone 6c afforded 2,3,5-trisubstituted phenols 10a and 10b, respectively.Structures 10a,b were assigned by their 1 H NMR and 13 C NMR spectra; only one new set of signals could be observed.In the 1 H NMR spectrum of 10a, the singlet at 2.20 ppm was assigned to the methyl group of 10a; in the 13 C NMR of 10a, the signal at 21.0 ppm was assigned to the same group.In the 1 H NMR of 10b, the triplet at 1.06 ppm and the quartet at 2.61 ppm were assigned to the ethyl group of 10b; in the 13 C NMR of 10b, the signals of this group appear at 14.4 ppm and 21.0 ppm.According to our previous mechanistic study 6 , if substituent R in a compound 3 is aliphatic, the pronounced difference in reactivities of the two methylenes alpha to the carbonyl, caused by the strong electronwithdrawing ability of the benzotriazole group, results in the regiospecificity of these reactions.b) The reactions of the intermediate 3a with chalcones 6a or 6b gave inseparable mixtures of regioisomers 10c/11c and 10d/11d, respectively.In the 1 H NMR spectra of each of these mixtures, two singlets were found near 2.00 ppm, which were assigned to the methyl groups.The ratio of compound 10c to 11c is 4:1, while the ratio of compound 10d to 11d is 1.6:1 according to the peak areas of the methyl groups in the 1 H NMR spectra.Two sets of signals could also be found in the 13 C NMR spectra: at 21.7 ppm and 21.0 ppm for the mixture of 10c and 11c, at 20.9 ppm and 21.0 ppm for the mixture of 10d and 11d.These observed ratios for 10c,d and 11c,d can be explained according to the high reactivity of the benzylic protons of 3a, which react via a 1,4-addition pathway with chalcones 6a or 6b.Thus, for 3a with R equal to phenyl, the regioselectivity of the reaction decreased and two regioisomers were obtained.
(iii) The reaction of intermediate 4 with α,β-unsaturated-γ-diketone 7b.Treatment of the intermediate 4 with α,β-unsaturated-γ-diketone 7b in acetonitrile in the presence of 5 N NaOH at room temperature overnight gave 2,3,5-trisubstituted phenol 8 in 50% yield (Table 1).In the 1 H NMR spectrum of the product, only one singlet at about 2.00 ppm could be found, which was assigned to the methyl group of the phenol 8.In the 13 C NMR spectrum, there is also only one signal at 12.9 ppm and it was assigned to the same group.As in this case R is an aliphatic group, there is a large difference between reactivities of the two positions alpha to the carbonyl group in the intermediate 4. Thus, this reaction is regiospecific, and only one product 8 was obtained.However, one point is noteworthy: the reaction of α,β-unsaturated diketone with α-substituted αbenzotriazolylmethyl ketones is very sensitive to the size of the α-substituent.For example, the yield of the compound 8 in this reaction (50%) is significantly lower than the yield of the analogous 2-unsubstituted product 12b (90%) (Table 1).When 3-(1H-1,2,3-benzotriazol-1-yl)-2pentanone 3d bearing the ethyl group in the α-position reacted with the compound 7b, the only result was a complex reaction mixture, which contained less than 10% of the desired product according to GC/MS.
(iv) The reactions of intermediates 3c,e,f,g with α,β−unsaturated-γ-diketones 7a,b.The reactions of α-benzotriazolylmethyl ketones 3c,e,f,g, with α,β-unsaturated-γdiketones 7a or 7b in acetonitrile in the presence of 5N NaOH gave 2,3,5-trisubstituted phenols 12a-e in yields of 33%-90%.The 1 H NMR spectra of 12a-e each showed only one set of signals for the appropriate protons.For example, in the 1 H NMR spectrum of product the 12a, two singlets at 2.34 ppm and 2.57 ppm were assigned for the two methyl groups.In the 13 C NMR of 12a, the signals of these groups appear at 10 ppm − 60 ppm.This demonstrated that this reaction sequence gives only one product.
Each of the two carbonyl groups present in α,β-unsaturated-γ-diketones 7a,b could be involved in a 1,4 conjugated addition.However, because both α,β-unsaturated-γ-di-ketones 7a,b are symmetrical and R in compounds 3c,e,f,g are aliphatic, thus providing a marked reactivity differences between two methylene groups α to the carbonyl group in the intermediates 3c,e,f,g, these reactions are regiospecific.
These reactions can be further divided into two classes according to the R 4 substituent: i) when R 4 is a methyl group, the α,β-unsaturated-γ-diketone 7a reacted with the intermediate 3e to give the product 12a in 33% yield; the low yield perhaps could be explained by the low stability of 7a under basic conditions; ii) when R 4 is a phenyl group, the reaction of α,β-unsaturated-γdiketone 7b with intermediates 3c,e,f,g gave the products 12b-e respectively, with excellent yields for 12b,c (R = H or Me) and moderate yields for 12d,e (R = n-Bu or benzyl) (Table 1).
These results demonstrate the effect of the R substituent: increasing bulk of the R group decreases product yield.Sodium hydroxide as a base in this reaction of 3 with 7 is preferable to potassium tert-butoxide.Being a strong enough base to complete the reaction successfully, sodium hydroxide does not cause the formation of byproducts, which could arise from the subsequent reactions of the acyl group in the products 12.On the other hand, the preparation of compound 12b using potassium tert-butoxide as a base afforded it only in 30% yield.However, the reactions of 3 with less reactive chalcones (discussed above) require stronger base, and in this case potassium tert-butoxide is preferable.( In summary, a novel synthetic route to 2,3,5-trisubstituted phenols was developed based on the two-step [1+2+3] construction of the phenol backbone from 1-[(trimethylsilyl)methyl]-1H-1,2,3-benzotriazole, an aliphatic or arylacetyl acid chloride and a chalcones or α,β-unsaturated-γdiketone.

Experimental Section
General Procedures.Melting points were determined on a hot-stage apparatus and are uncorrected.NMR spectra were recorded in CDCl 3 or DMSO-d 6 with TMS as the internal standard for 1 H (300 MHz) or a solvent as the internal standard for 13 C (75 MHz).Microanalyses were performed on a Carlo Erba -1106 elemental analyzer.Benzene and toluene were dried over molecular sieves.Column chromatography was conducted with silica gel 200−425 mesh.Trimethylsilylmethylbenzotriazole 1 was synthesized according to the procedure already reported. 10Compound 3e was prepared according to the reported procedure 6 .Compounds 3f and 3g were prepared according to the reported procedure 11 .